Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

Matthew J Armstrong; Diana Hull; Kathy Guo; Darren Barton; Jonathan M Hazlehurst; Laura L Gathercole; Maryam Nasiri; Jinglei Yu; Stephen C Gough; Philip N Newsome; Jeremy W Tomlinson

doi:10.1016/j.jhep.2015.08.038

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

Matthew J Armstrong, Diana Hull, Kathy Guo, Darren Barton, Jonathan M Hazlehurst, Laura L Gathercole, Maryam Nasiri, Jinglei Yu, Stephen C Gough, Philip N Newsome, Jeremy W Tomlinson

Research output: Contribution to journal › Article › peer-review

169 Citations (Scopus)

249 Downloads (Pure)

Abstract

OBJECTIVE: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.

DESIGN: 14 patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.

RESULTS: Liraglutide reduced BMI (-1.9 vs. +0.04 kg/m²;p<0.001), HbA1c (-0.3 vs. +0.3%;p<0.01), cholesterol-LDL (-0.7 vs. +0.05 mmol/L;p<0.01), ALT (-54 vs -4.0 IU/L;p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin;p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum NEFA; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic DNL in-vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).

CONCLUSIONS: Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.

Original language	English
Pages (from-to)	399–408
Number of pages	10
Journal	Journal of Hepatology
Volume	64
Issue number	2
Early online date	21 Sept 2015
DOIs	https://doi.org/10.1016/j.jhep.2015.08.038
Publication status	Published - Feb 2016

Keywords

Glucagon-like peptide 1
Non-alcoholic fatty liver
Insulin sensitivity
Adipose tissue
Lipolysis

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jhep.2015.08.038Licence: Creative Commons: Attribution (CC BY)

ArmstrongM2015GlucagonFinal published version, 1.15 MBLicence: Creative Commons: Attribution (CC BY)

Glucocorticoid Metabolism and the Control of Metabolic Phenotype
Tomlinson, J.
Medical Research Council
1/10/09 → 30/09/14
Project: Research Councils

Cite this

@article{485809727f0a4096b9a33236a0f9f816,

title = "Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis",

abstract = "OBJECTIVE: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.DESIGN: 14 patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.RESULTS: Liraglutide reduced BMI (-1.9 vs. +0.04 kg/m2;p<0.001), HbA1c (-0.3 vs. +0.3%;p<0.01), cholesterol-LDL (-0.7 vs. +0.05 mmol/L;p<0.01), ALT (-54 vs -4.0 IU/L;p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin;p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum NEFA; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic DNL in-vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).CONCLUSIONS: Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.",

keywords = "Glucagon-like peptide 1, Non-alcoholic fatty liver, Insulin sensitivity, Adipose tissue, Lipolysis",

author = "Armstrong, {Matthew J} and Diana Hull and Kathy Guo and Darren Barton and Hazlehurst, {Jonathan M} and Gathercole, {Laura L} and Maryam Nasiri and Jinglei Yu and Gough, {Stephen C} and Newsome, {Philip N} and Tomlinson, {Jeremy W}",

year = "2016",

month = feb,

doi = "10.1016/j.jhep.2015.08.038",

language = "English",

volume = "64",

pages = "399–408",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "2",

}

TY - JOUR

T1 - Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

AU - Armstrong, Matthew J

AU - Hull, Diana

AU - Guo, Kathy

AU - Barton, Darren

AU - Hazlehurst, Jonathan M

AU - Gathercole, Laura L

AU - Nasiri, Maryam

AU - Yu, Jinglei

AU - Gough, Stephen C

AU - Newsome, Philip N

AU - Tomlinson, Jeremy W

PY - 2016/2

Y1 - 2016/2

N2 - OBJECTIVE: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.DESIGN: 14 patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.RESULTS: Liraglutide reduced BMI (-1.9 vs. +0.04 kg/m2;p<0.001), HbA1c (-0.3 vs. +0.3%;p<0.01), cholesterol-LDL (-0.7 vs. +0.05 mmol/L;p<0.01), ALT (-54 vs -4.0 IU/L;p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin;p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum NEFA; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic DNL in-vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).CONCLUSIONS: Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.

AB - OBJECTIVE: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.DESIGN: 14 patients were randomised to 1.8mg liraglutide or placebo for 12-weeks of the mechanistic component of a double-blind, randomized, placebo-controlled trial (ClinicalTrials.gov-NCT01237119). Patients underwent paired hyperinsulinaemic euglycaemic clamps, stable isotope tracers, adipose microdialysis and serum adipocytokine/metabolic profiling. In vitro isotope experiments on lipid flux were performed on primary human hepatocytes.RESULTS: Liraglutide reduced BMI (-1.9 vs. +0.04 kg/m2;p<0.001), HbA1c (-0.3 vs. +0.3%;p<0.01), cholesterol-LDL (-0.7 vs. +0.05 mmol/L;p<0.01), ALT (-54 vs -4.0 IU/L;p<0.01) and serum leptin, adiponectin, and CCL-2 (all p<0.05). Liraglutide increased hepatic insulin sensitivity (-9.36 vs. -2.54% suppression of hepatic endogenous glucose production with low-dose insulin;p<0.05). Liraglutide increased adipose tissue insulin sensitivity enhancing the ability of insulin to suppress lipolysis both globally (-24.9 vs. +54.8 pmol/L insulin required to ½ maximally suppress serum NEFA; p<0.05), and specifically within subcutaneous adipose tissue (p<0.05). In addition, liraglutide decreased hepatic DNL in-vivo (-1.26 vs. +1.30%; p<0.05); a finding endorsed by the effect of GLP-1 receptor agonist on primary human hepatocytes (24.6% decrease in lipogenesis vs. untreated controls; p<0.01).CONCLUSIONS: Liraglutide reduces metabolic dysfunction, insulin resistance and lipotoxicity in the key metabolic organs in the pathogenesis of NASH. Liraglutide may offer the potential for a disease-modifying intervention in NASH.

KW - Glucagon-like peptide 1

KW - Non-alcoholic fatty liver

KW - Insulin sensitivity

KW - Adipose tissue

KW - Lipolysis

UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713865/

U2 - 10.1016/j.jhep.2015.08.038

DO - 10.1016/j.jhep.2015.08.038

M3 - Article

C2 - 26394161

SN - 0168-8278

VL - 64

SP - 399

EP - 408

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 2

ER -

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatophepatitis

Abstract

Keywords

UN SDGs

Access to Document

Fingerprint

Projects

Glucocorticoid Metabolism and the Control of Metabolic Phenotype

Cite this